It is known that water insoluble drugs can be rendered injectable by formulating them into aqueous suspensions of phospholipid-coated microcrystals. Haynes, U.S. Pat. No. 5,091,188 and U.S. Pat. No. 5,091,187, disclosed a method of coating pharmaceutical compounds with a phospholipid layer that makes water insoluble drugs able to be contained within an aqueous medium, and therefore suitable for injection in a mammal.
Baurain et al., U.S. Pat. No. 4,973,467 describes the preparation of microcrystals of ginkolide B, kadsurenone, amphotericin B, and nystatin. Baurain et al. prepared microcrystals by the common method of forming a lipid film in a flask by dissolving the lipids to be used in organic solvent, evaporating the solvent, and then sonicating in the presence of the active compound to produce microcrystals sized between 0.1 xcexcm and 2 xcexcm.
Animal husbandry operations which manage large numbers of animals have been unable to realize the benefits of the prior technology because it has not been successfully applied on a large scale. The procedures disclosed by Haynes and others have had limited commercial practicability since the methods involve the use of sonication or other processes which are inappropriate or impractical for producing commercially advantageous quantities of product.
The present invention provides a method suitable for economically producing yields of up to thousands of liters of pharmaceutical compositions for the sustained release of a pharmacologically active compound. The method can be applied with a commercial scale homogenizer, or any instrument or technique which provides the necessary forces to effectively coat the pharmacologically active compound with the lipid suspension.
Furthermore, the compositions of the prior art have relied on commonly available forms of phospholipid mixtures which are highly purified and prohibitively expensive for use on a commercial scale. The present invention discloses a method for isolating a composition of lipids from egg yolk which results in a suspension of lipids which can be economically produced, and can be used to coat a pharmacologically active compound to produce the microcrystals of the present invention. These microcrystals exhibit several beneficial characteristics, including a longer sustained release time and the ability to sharply decrease the toxicity of drug compounds. These microcrystals may be formed into an injectable suspension for subcutaneous injection into a mammal. The suspension may be syringeable and therefore suitable for subcutaneous injection.
One skilled in the art will realize that the microcrystals of this invention can be administered to the mammal in a variety of other ways including, but not limited to, skin patches, ocular inserts, shooting through the skin at high velocity with a medical xe2x80x9cair gun,xe2x80x9d suppositories, or simply providing the compounds in a mammal""s food and water.
It has been previously thought that it is desirable to produce a composition of microcrystals having homogeneous microcrystals of a very small size. Previously, it has been believed that it is desirable to produce microcrystals below 1 xcexcm, or at least below 2 xcexcm or 3 xcexcm. The present invention discloses that unexpected benefits, including benefits in timed release delivery, can be realized by producing a composition which contains microcrystals of varying sizes. The present invention discloses compositions wherein at least 50 percent of the microcrytals are from about 0.5 xcexcm to about 3.0 xcexcm in diameter, at least ten percent of the microcrystals are from about 3.0 xcexcm to about 10 xcexcm in diameter, and the compositions contain microcrystals which are greater than about 10 xcexcm in diameter. In a preferred embodiment, at least about 50 percent of the microcrystals will be from about 0.5 xcexcm to about 3 xcexcm in diameter, from about thirty to about forty percent of the microcrystals will be from about 3 xcexcm to about 10 xcexcm in diameter, and the composition contains microcrystals which are greater than about 10 xcexcm in diameter. We have found that by utilizing microcrystals of these varying sizes sustained release times of as long as 10-12 days can be obtained. The person of skill in the art will readily realize that even presently known lipid compositions may be put into the novel compositions claimed herein to realize these benefits. The invention teaches novel compositions which are mixtures of microcrystals of varying sizes as disclosed herein.
The present invention also discloses methods for treating infections in mammals. In preferred embodiments, methods are provided for treating respiratory diseases in mammals, in particular, infections of the respiratory tract. In particularly preferred embodiments, methods are provided for treating bovine respiratory disease (commonly known as xe2x80x9cshipping feverxe2x80x9d), kennel cough in dogs, and Potomac fever in horses. In another particularly preferred embodiment, methods are provided for treating infections of the respiratory tract in cats.
Prior methods of treating infections in animals have centered on the regular and repeated administration of antibiotics to the mammal until the infection was eradicated, sometimes by incorporating the drug into the animal""s food or water, by oral administration in a paste or with a balling gun, or by repeated injections. Therapeutic regimens often failed due to a failure on the part of the animal owner to follow the prescribed regimen. The present invention provides a method of treating infections which requires only a single administration of the microcrystal compositions of the present invention. The microcrystal composition may be an injectable syringeable suspension. The administration can be delivered by an animal care professional and does not require further participation by the owner for a successful result of the therapy, thereby eliminating issues of therapy noncompliance by the owner as a reason for failure of the therapy. The present methods are applicable to a variety of mammals including, but not limited to, bovines, equines, porcines, canines, and felines. The person of skill in the art will readily realize that the methods herein disclosed will find applicability to a wide variety of mammals.
The person of skill in the art will also readily realize that the compositions and techniques described herein can be applied to a wide variety of pharmacologically active compounds. Various antibiotics, anesthetics, anti-inflammatory agents, and anti-protozoan agents may all be incorporated into a microcrystal suspension, as may other chemical compounds of varied uses which will be apparent to those of skill in the art.
We have also observed that pharmacologically active compounds which are coated with the phospholipid composition of the present invention are able to attach to blood cells. In this case the pharmacologically active compound is found associated with the blood cells in blood analysis assays. This characteristic of the microcrystals of the present invention serves to facilitate the delivery of pharmacologically active compound to the body tissues.
The present invention realizes a substantial advance in the field of microcrystal technology by providing novel lipid compositions for coating microcrystals of useful drugs. These novel compositions result in pharmaceutical suspensions containing phospholipid coated microcrystals which offer significantly longer sustained release times than those of the prior art. These compositions offer the additional and important benefit of sharply reducing the toxicity of many useful pharmaceutical compounds which are underutilized due to concerns about their toxicity.
The present invention also provides new methods for manufacturing suspensions of microcrystals which contain pharmaceutically active compounds encapsulated in a phospholipid layer on a commercial scale. The suspensions may be made suitable for injection. Various water insoluble and pharmaceutically active compounds may be produced in the form of these phospholipid coated microcrystals. The methods are suitable for producing thousands of liters of microcrystal product, allowing the technology to be utilized on a commercial scale.
The present invention also provides methods for treating infections in a variety of mammals which involve the administration of the microcrystals produced by these methods. In preferred embodiments, the infection may be a bacterial, fungal, protozoa, or any type of parasitic organism which has invaded the body. In a preferred embodiment, the microcrystal suspension may be made into an injectable syringeable suspension and the administration accomplished by subcutaneous injection. These methods offer the distinct advantages of effective single dose therapies to cure infections, eliminate noncompliance as a barrier to drug efficacy, sharply decrease the toxicity of drug compounds, and avoid further stress and discomfort to the treated animal.
The present invention is directed towards novel pharmaceutical compositions for the sustained release of pharmacologically active compounds, and methods of their manufacture. The pharmaceutical compositions contain microcrystals of pharmacologically active compounds which are encapsulated within a phospholipid bilayer. The phospholipid bilayer contains a unique combination of phospholipids which imparts unexpected beneficial properties.
In particular, the present invention provides a composition of lipids used in coating a pharmacologically active compound which is from about 40 percent to about 80 percent by weight of phosphatidylcholine, and from about 10 percent to about 30 percent by weight of phosphatidylethanolamine. In preferred embodiments, the composition will comprise from about 50 percent to about 68 percent by weight phosphatidylcholine, and from about 15 percent to about 25 percent by weight phosphatidyl ethanolamine.
The present invention also provides pharmaceutical compositions which contain a suspension of microcrystals contained within a phospholipid layer which is made of any of the compositions of lipids described above. The microcrystals are a solid, crystalline form of the particular pharmacologically active compound of interest. The suspension may be made suitable for injection into a mammal, and may be made syringeable as well.
The present invention also provides pharmaceutical suspensions of microcrystals which contain a pharmacologically active compound contained within a phospholipid layer. In this aspect, at least about fifty percent of the microcrystals are from about 0.5 xcexcm to about 3.0 xcexcm in diameter, at least about 10 percent of the microcrystals are from about 3 xcexcm to about 10 xcexcm in diameter, and at least about 90 percent of the microcrystals are less than about 10 xcexcm in diameter. The suspension also contains microcrystals which are greater than about 10 xcexcm in diameter. In a preferred embodiment, at least about fifty percent of the microcrystals are from about 0.5 xcexcm to about 3.0 xcexcm in diameter, from about thirty to about 40 percent of the microcrystals are from about 3.0 xcexcm to about 10 xcexcm in diameter, and the suspension contains microcrystals which are greater than about 10 xcexcm in diameter. In a particularly preferred embodiment, at least about 1 percent of the microcrystals are greater than about 10 xcexcm in diameter.
The present invention also provides methods of manufacturing the pharmaceutical compositions of the present invention for the sustained release of pharmacologically active compounds. The compositions contain microcrystals which contain pharmacologically active compounds contained within a phospholipid layer. The method includes the steps of forming a lipid suspension which contains the pharmacologically active compound and passing the lipid suspension with the pharmacologically active compound through a homogenizer at high pressure to coat the compound with the lipid suspension and produce a suspension of microcrystals where at least about fifty percent of the microcrystals are from about 0.5 xcexcm to about 3 xcexcm in diameter, and at least about ten percent of the microcrystals are from about 3 xcexcm to about 10 xcexcm in diameter, and the suspension contains microcrystals which are greater than about 10 xcexcm in diameter. In a preferred embodiment, at least about 25 percent of the microcrystals will be greater than about 3 xcexcm in diameter. In another preferred embodiment, at least about 25 percent of the microcrystals will be from about 3 xcexcm to about 10 xcexcm in diameter.
In another aspect, there are provided methods for manufacturing the pharmaceutical compositions of the present invention for the sustained release of pharmacologically active compounds. The compositions contain microcrystals which contain pharmacologically active compounds contained within a phospholipid layer. The methods include the steps of forming a lipid suspension, and contacting the lipid suspension with the pharmacologically active compound to coat the pharmacologically active compound with the lipid suspension and produce a suspension of microcrystals where at least about fifty percent of the microcrystals are from about 0.5 xcexcm to about 3 xcexcm in diameter, and at least about ten percent of the microcrystals are from about 3 xcexcm to about 10 xcexcm in diameter, and the suspension contains microcrystals which are greater than about 10 xcexcm in diameter. In a preferred embodiment, at least about 25 percent of the microcrystals will be greater than about 3 xcexcm in diameter. In other preferred embodiments, at least about 25 percent of the microcrystals will be from about 3 xcexcm to about 10 xcexcm in diameter.
The method produces water insoluble drugs which are coated with the phospholipid suspension and which have been modified such that they can be safely injected and have a sustained release from an injection site in a mammal, and provide an effective therapy for a variety of disease states. The microcrystals can be produced within the above stated size distribution range which serves to increase the sustained release time of the pharmacologically active compound they contain.
In one embodiment of the method, the lipid suspension is passed through a homogenizer repeatedly at high pressure. In a preferred embodiment, it is passed through a homogenizer three times at high pressure. In other embodiments, the lipid suspension may be passed through a homogenizer a number of times necessary to obtain a microcrystal suspension which lacks clumping, contains particles within the desired size ranges indicated above, and is free-flowing.
The pharmacologically active compound may be an antibiotic. The antibiotic may be a cephalone, tilmicosin, or nitazoxanide. The antibiotic may also be a floroquinolone such as ofloxacin, sarafloxicin, or ciprofloxicin. The antibiotic may also be a cephalosporin such as cefazolin, cefuroxine or a derivative of cefuroxine, cefoperazone, or cefoclor. In other embodiments, the antibiotic may be a tetracycline such as oxytetracycline. The pharmacologically active compound may also be a floroquinolone and a cephalosporin which have been combined to form a single molecule. The pharmacologically active compound may also be an anti-inflammatory agent, such as flunixin. In other embodiments, the pharmaceutical composition may be an anesthetic, such as propofal, or an anti-protozoan agent, such as nitazoxanide. The suspension of microcrystals produced by the manufacturing method may also be sterilized with radiation or another sterilization method. In a preferred embodiment, the suspension of microcrystals is sterilized with gamma radiation. Persons of skill in the art will readily see that the techniques and principles disclosed can be applied to a variety of water insoluble pharmaceutical products and chemicals to produce microcrystals which are useful for a wide variety of purposes. The techniques and principles may also be applied to water soluble compounds which have been modified in order to behave more like water insoluble compounds.
The pharmacologically active compounds described above have formal, chemical names which are hereby provided for reference. Tilmicosin is chemically known as 20-deoxo-20-(3,5-dimethyl piperidinyl)-1-yl desmycosin. Ciprofloxacin is chemically known as 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline carboxylic acid. Cefazolin is chemically known as [(6R-trans)-3[[5-methyl-1,3,4-thiadiazol-2-yl) thio]methyl]-8-oxo-7-[(1H-tetrazol-1-yl acetyl)-amino]-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid]. Cefaclor is chemically known as 7-[(aminophenylacetyl)amino]-3-chloro-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid. Cefoperazone is chemically known as 7-[D-(xe2x88x92)-xcex1-(4-ethyl-2,3-dioxo-1-piperzine carboxamido)-xcex1-(4-hydroxylphenyl) acetamido]-3[[1-methyl-1H-tetra-zol-5-yl) thio]methyl]-3-cephem-4-carboxylic acid. Cefuroxine is chemically known as [6R-[6xcex1,7xcex2(Z)]]-3-[[(aminocarbonyl)oxy]methyl]-7-[[2-furanyl(methoxyimino) acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid. Oxytetracycline is chemically known as 4-(dimethylamino)-1,4,4a,5,-5a ,6,11,12a-octahydro-3,5,6,10,12,12a-hexahydroxy-6-methyl-1,11-dioxo-2-naphthalenecarboxamide. Ofloxacin is chemically known as (xc2x1)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido-[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid. Flunixin is chemically known as 2-[[2-methyl-3-(trifluoromethyl) phenyl]amino]-3-pyridine carboxylic acid. Propofal is chemically known as 2,6-bis(1-methylethyl) phenol. Cephalone (cephaquinolone) is chemically known as 7[(1-cyclopropyl-6-fluoro-7-(4-ethyl piperazine-1-yl-1-, 4 dihydro-4-oxoquinoline-3-yl) carboxamido] cefalosporanic acid. Nitazoxanide (NTZ) is chemically known as 2-(acetyloxy)-N-(5-nitro-2-thiazolyl) benzamide. Sarafloxacin is chemically known as 6-Fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid.
The present invention also provides a method for treating an infection in a mammal. The method contains the steps of administering to the mammal an effective dose of a suspension containing microcrystals which contains a pharmacologically active compound within a phospholipid layer. At least about 50 percent of the microcrystals are from about 0.5 xcexcm to about 3 xcexcm in diameter, at least about ten percent of the microcrystals are from about 3 xcexcm to about 10 xcexcm in diameter, and the suspension contains microcrystals that are greater than about 10 xcexcm in diameter. In a preferred embodiment, at least about 25 percent of the microcrystals will be from about 3 xcexcm to about 10 xcexcm.
In preferred embodiments, the pharmacologically active compound may be any of the pharmacologically active compounds described herein.
In a preferred embodiment, the infection may be a respiratory disease and may be treated with microcrystals containing any of the above named compounds. In a particularly preferred embodiment, the infection may be bovine respiratory disease and the pharmacologically active compound may be oxytetracycline. In another particularly preferred embodiment, the disease may be xe2x80x9ckennel cough,xe2x80x9d the mammal a canine, and the pharmacologically active compound tilmicosin.
The infection may also be caused by a protozoa and the microcrystal may contain an anti-protozoa agent such as nitazoxanide (NTZ). The infection may also be caused by a fungus and the pharmacologically active compound contained in the microcrystal may be an anti-fungal agent. The person of skill in the art will readily see that the microcrystals may contain a wide variety of pharmacologically active compounds which may be used to treat a wide variety of diseases.
In preferred embodiments, the suspensions of the present invention may be made into an injectable syringeable form and administered to the mammal by parenteral administration. The mammal may be a bovine, an equine, a porcine, a canine, a feline, or any mammal.
In another aspect, the invention provides a method for treating inflammation in a mammal. In this aspect, the pharmacologically active compound will be an anti-inflammatory agent contained within a phospholipid layer. In a preferred embodiment, the anti-inflammatory agent may be flunixin.
In another aspect of the invention, the above method may be a method for treating pain in a mammal. In this aspect, the microcrystals contain an anesthetic. In a preferred embodiment, the anesthetic may be propofal. All of the pharmaceutical compounds described herein may be made into a syringeable injectable form and administered to the mammal parenterally.
The present invention also provides a method for isolating from a lipid source a composition of lipids suitable for coating microcrystals. The method includes the steps of performing a lipid extraction on the lipid source with acetone, and a lipid extraction on the lipid source with ethyl alcohol. In a preferred embodiment, the lipid source is egg yolk.
The present invention also provides a pharmaceutical composition which contains microcrystals, which are compositionally from about 10 percent to about 30 percent by weight of a pharmacologically active compound, and from about 15 percent to about 30 percent of a phospholipid syrup. In a preferred embodiment, the microcrystals may be compositionally from about 25 percent to about 30 percent by weight of a pharmacologically active compound, and about 20 percent of a phospholipid syrup. In a preferred embodiment, the pharmacologically active compound may be an antibiotic, such as oxytetracycline. In other embodiments, the pharmacologically active compound may be any of the compounds described herein.
The person of skill in the art will realize that the techniques and principles disclosed can be used to treat a variety of diseases in many types of mammals.